Of all human medical health conditions, cardiovascular diseases are the single largest cause of morbidity and death. It is well known that the blood contains lipoproteins. These are particles responsible for transporting non-aqueous lipids throughout the body, and are generally classified into four major categories with the associated general functions; chylomicrons, large triglyceride containing lipoproteins produced by the intestine during the processes of absorbing dietary fat, very low density lipoproteins (VLDL) triglyceride-rich lipoproteins produced by the liver and facilitates transport of triglycerides to muscle and adipose tissue for energy and storage, low density lipoproteins (LDL), cholesterol-rich particles that transport cholesterol to cells for growth, repair, production of bile acids, or for storage as cholesteryl esters as a reservoir of cholesterol for steroid production, and finally high density lipoprotein, a phospholipid-rich lipoprotein, that facilitates removal of excess cholesterol from cells. Each type of lipoprotein is comprised of polar and nonpolar lipids as well as amphipathic apolipoproteins.
Human epidemiologic and clinical studies have demonstrated the importance of low levels of LDL-cholesterol (LDL-C) in the prevention and treatment of cardiovascular diseases. And Epidemiologic evidence has also shown that high levels of HDL-cholesterol (HDL-C) play a role in preventing cardiovascular disease. It is also believed that low levels of very low density lipoprotein-cholesterol (VLDL-C) and plasma triglycerides are important in the prevention of cardiovascular diseases.
It is well known that reduction of LDL-C is an important aspect of medical treatment to prevent or delay the onset of cardiovascular diseases as well as to treat existing cardiovascular diseases. More recently, it has been recognized that aggressive lowering of LDL-C is beneficial in delaying and preventing additional episodes of cardiovascular disease. Although LDL receives primary attention for clinical management, growing evidence indicates that other factors play important roles in determining risk for cardiovascular disease, for example, total cholesterol levels, HDL levels, blood pressure, and smoking status. Consideration of these risk factors is important in determining treatment goals. In particular, it is crucial for persons with known coronary heart disease (CHD) to control multiple risk factors responsible for the worsening of CHD.
Risk of cardiovascular disease is estimated in a variety of ways by a number of prognostic indicators. The Framingham Risk Score is based on data obtained from the Framingham Heart Study and is used to estimate the 10-year cardiovascular risk of an individual. The Framingham Risk Score is a calculated estimated risk for developing fatal or non-fatal cardiovascular event based on a composite score based on a pre-existing risk factors, including: age, gender, systolic blood pressure level (+/−treatment), HDL cholesterol level, and smoker status. A patient's risk score gives and indication of the likely benefits of prevention and also can be a useful metric to determine the effects of treatments.
The 2004—Updated National Cholesterol Education Program Adult Treatment Panel III (2004—Updated NCEP ATPIII) guidelines present treatment guidelines for patients with elevated LDL-C, triglycerides and other genetic or environmental risk factors. Briefly, the 2004—updated NCEP ATP III treatment guidelines recommend LDL-C lowering guidance based on pre-existing conditions. The updated guidelines add the use of Framingham projections of a 10-year absolute CHD risk to identify patients for more intensive treatment. For subjects with 0 or 1 risk factors, an LDL-C of less than 160 mg/dL is recommended. For subjects with two or more risk factors and with a Framingham 10-year risk of less than 10 percent, an LDL-C of less than 130 mg/dL is recommended. For subjects with two or more risk factors and with a Framingham 10-year risk of 10-20%, or existing cardiovascular heart disease, or cardiovascular heart disease risk equivalents, or a Framingham 10-year risk of greater than 20%, an LDL-C of less than 100 mg/dL is recommended. CHD risk equivalents include other clinical forms of atherosclerotic disease (peripheral arterial disease, abdominal aortic aneurysm, and symptomatic carotid artery disease); diabetes; and the presence of multiple risk factors that confer a 10-year Framingham risk for CHD of ≥20%. For subjects with established cardiovascular disease and also are diabetic, or are also smokers, or also have low levels of HDL-C and high levels of blood triglycerides, or also have metabolic syndrome, or also have multiple risk factors, an LDL-C of less than 70 mg/dL is recommended.
The difficulty of lowering the LDL-C level to less than 100 mg/dL or less in patients with known CHD has been well documented. Achieving the updated NCEP ATP-III guidelines recommendation to reduce LDL-C levels to lower than 70 mg/dL for persons at very high risk, is even more difficult.
In Europe, the Third Joint European Task Force (TJETF) provides recommendations or guidelines for lowering LDL-C based on existing LDL-C levels, total cholesterol levels, type 2 diabetes, systolic blood pressure, diastolic blood pressure, 10-year risk score of a fatal cardiovascular event, or preexisting atherosclerotic disease. Recommendations are also provided for patients having a combination of conditions, such as a known 10-year risk score of fatal cardiovascular disease plus elevated plasma total cholesterol or LDL cholesterol levels. Specifically the TJETF recommends reaching an LDL-C of less than 115 mg/dL if a subject's 10-year risk of cardiovascular disease is less than 5 percent, or has a 10-year risk of cardiovascular disease of greater than or equal to 5 percent and also has an existing total cholesterol of greater than or equal to 190 mg/dL or an existing LDL-C of greater than or equal to 115 mg/dL. The TJETF guidelines recommends reaching an LDL-C of less than 100 mg/dL if a subject has atherosclerotic disease, or Type 2 diabetes, or a total cholesterol greater than or equal to 320 mg/dL, or an LDL-C greater than or equal to 240 mg/dL, or has systolic blood pressure of greater than or equal to 180 mm Hg, or has diastolic blood pressure of greater than or equal to 110 mm Hg, or has a 10-year risk of cardiovascular disease of greater than or equal to 5 percent plus a total cholesterol of less than 190 mg/dL and an LDL-C less than 115 mg/dL.
Although statins are drugs of choice to lower LDL-C, not all patients can tolerate statins or can tolerate a high statin dose. In addition, approximately half of all patients on stable statin doses do not reach recommended LDL-C lowering goals, (See, Centralized Pan-European Survey on the Undertreatment of Hypercholesterolemia in Patient Using Lipid Lowering Drugs, The Cepheus-Greece Survey, Angiology (2010), Vol. 61 (5), pp 465-474 and the 2004-updated NCEP ATPIII guidelines.).
Furthermore, it is well recognized, that the doubling of a statin dose in a patient already on a statin, has limited effect on further LDL-C lowering while increasing safety issues associated with a high statin dose. The literature teaches that lowering cholesterol beyond that achieved with a stable statin dose is difficult. McKenney reported that statins have a nonlinear dose-response relationship such that doubling the dose of a particular statin provides only an additional 6% further lowering of LDL-C (American Journal of Therapeutics (2004), Vol. 11, pp 55-59). While other treatments can further lower LDL-C, this further reduction is often not enough to bring these patients' LDL-C level down to goal. For example, the combination of a stain plus a fibrate, such as fenofibrate has little effect or has a negative effect on LDL-C beyond the statin alone. The combinations of stains with bile acid sequestrants, such as cholestyramine, can result in lower LDL-C, however the reduction is often insufficient to reach a desirable LDL-C goal and compliance for bile acid sequestrants with patients is poor. Although agents such as Zetia, that block cholesterol absorption from the intestine, have shown improved LDL-C lowering when given with a statin, further lowering of LDL-C levels may be needed.
The goal for LDL-C levels under the current guidelines is guided by an assessment of the risk for developing cardiovascular heart disease or having a recurrence of a cardiovascular event.
Therefore there is a need for additional agents to reduce a patients risk for developing cardiovascular heart disease or having a recurrence of a cardiovascular event.